This invention relates to a new class of antibiotics which may be generically represented by the following structural formula (I): ##STR1## wherein the dotted line indicates provision for both .DELTA..sup.2 and .DELTA..sup.3 embodiments; A is S, O, CH.sub.2, SO, or NR.sup.7 (R.sup.7 is selected from the group consisting of hydrogen, alkyl, formyl, acyl, thioacyl, alkylsulfonyl and arylsulfonyl); X is OH, .dbd.O, SH, .dbd.NH, NH.sub.2, or NHR.sup.7 ; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl; aryl; aralkyl; heteroaryl and heteroaralkyl (mono- and bicyclic) wherein the heterocyclic moiety comprises 4-10 ring atoms and the hetero atom (or atoms) is O, N or S; and wherein the ring or chain substituent is selected from: amino, carboxy, hydroxy, alkoxy, carbalkoxy, lower alkyl, heteroaryl, and substituted amino such as mono- and di-alkylamino, and acylamino; and perhaloalkyl; examples of such substituents, R.sup.1 and R.sup.2, are: methyl, tri-fluoromethyl, phenyl, substituted phenyl, benzyl and the like; R.sup.3 is selected from the group consisting of hydrogen, alkoxy, alkylthio and halogen such as fluoro and bromo; R.sup.5 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl; aryl; aralkyl, heteroaryl and heteroaralkyl wherein the heterocyclic moiety comprises 4-6 ring atoms and the hetero atom (or atoms) is O, N or S; wherein the ring on chain substituent is selected from: amino, carboxy, hydroxy, alkoxy, carbalkoxy, lower alkyl, heteroaryl, and substituted amino such as mono- and di-alkylamino, and acylamino; examples of such substituents, R.sup.5 are: .beta.-aminoethyl, .beta.-hydroxyethyl, phenyl, substituted phenyl, benzyl, phenethyl and the like; and R.sup.6 is selected from the group consisting of PO(OH).sub.2, SO.sub.2 (OH), SO.sub.2 NH.sub.2 and derivatives thereof, [see copending, commonly assigned U.S. patent application, Ser. No. 410,831 filed Nov. 8, 1973, incorporated herein by reference for definition of R.sup.6 ], and COXR.sup.8 wherein X is oxygen or sulphur and R.sup.8 is, inter alia, representatively selected from the group consisting of hydrogen, trialkylsilyl, and the pharmaceutically acceptable salt, ester and amide moieties known in the antibiotic bicyclic .beta.-lactam art such as sodium, potassium, pivaloyloxymethyl, and the like.
There is a continuing need for new antibiotics. For, unfortunately, there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to strains of pathogens which are resistant to the exploited antibiotic. In addition, the known antibiotics suffer from the disadvantage that they are only effective against certain types of microorganisms. Accordingly, the search for new antibiotics has continued.
unexpectedly, it has been discovered that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems. It will be recognized from the above generic representation (I) that the principal novel features of the compounds of the present invention are the substituents at the 7- and 3-positions. It will also be noted, except where expressly stated, that the balance of the cephalosporin or cephalosporin-like structure (I) is well-known in the relevant art; likewise the substituents R.sup.3 and R.sup.6 are well-known as exemplified by the following U.S. Patents and co-pending, commonly assigned U.S. patent applications which are incorporated herein by reference [U.S. patent application, Ser. No. 410,831 filed Nov. 8, 1973].
Thus it is an object of the present invention to provide a novel class of antibiotics which includes, inter alia, species having the basic nuclear structure of the cephalosporins but which are characterized by having a substituted thio radical at the 3-position of the six-membered ring and a substituted methyl radical at the 7-position of the .beta.-lactam ring. These antibiotics are active against a broad range of pathogens, which representatively include gram positive bacteria such as Staphylococcus aureus, Streptococcus pyrogenes, and gram negative bacteria such as E. coli and Salmonella and Proteus mirabilis and Proteus morganii. Further objects of this invention are to provide chemical processes for the preparation of such compounds; intermediates useful in preparing such compounds; pharmaceutical compositions comprising such compounds; and to provide methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.